Liquid formulations for the prevention and treatment of mucosal diseases and disorders

ABSTRACT

Stable, viscous, mucoadhesive aqueous compositions which are useful for the prevention and treatment of ulcerative, inflammatory, and/or erosive disorders of mucous membranes, especially mucositis.

Continuation-in-part of U.S. patent application Ser. No. 10/077,459,filed Feb. 15, 2002, which in turn claims priority under 35 U.S.C.Section 119(e) to U.S. Provisional Application Ser. No. 60/269,049,filed Feb. 15, 2001, now abandoned. The content of each application ishereby incorporated by reference into the present disclosure.

FIELD OF THE INVENTION

The present invention relates to compositions and methods of manufactureof stable, viscous, mucoadhesive liquid and mucoadhesive gelformulations, and the use of these compositions to coat mucocutaneoussurfaces, in particular the oral cavity, to prevent and/or treat mucosaldiseases and disorders, including those which are ulcerative,inflammatory, and/or erosive, especially mucositis induced bychemotherapy and/or radiation therapy. The liquid dosage forms aresufficiently mobile to coat a wide area of the mucosal surface, but arealso mucoadhesive and viscous to provide prolonged retention on thesurface of the mucosa. The liquid compositions may be used without aknown pharmaceutically active compound. One or more pharmaceuticallyactive compounds may be included in the formulation to provideadditional benefit in the topical treatment of diseases and disorders ofthe mucosa.

BACKGROUND OF THE INVENTION

Mucous membranes provide a protective layer on the surface of severalbody cavities, such as the oral cavity, the nasal cavity, thegastrointestinal and respiratory tracts, the vagina, and the bladder.Cells within or glands adjacent to these membranes secrete mucus, afluid or gel primarily composed of water, lipids, inorganic salts andmucin glycoproteins, which serve to form a protective barrier to inhibitpassage of harmful materials to the underlying tissue. There are severaldiseases and disorders of these mucosal surfaces which can result insevere pain, irritation, erythema, and/or ulceration. Examples of suchdiseases in the oral cavity include aphthous ulcers, bullous pemphigoid,oral lichen planus, and oral mucous membrane contact dermatitis. Manyother ulcerative mucocutaneous diseases are known. There are alsopainful ulcerative disorders of mucosal surfaces which result as anadverse side-effect in certain therapies, such as chemotherapy andradiation therapy. Mucositis is an adverse side-effect which impacts theoral cavity in patients undergoing therapy for a number of conditionsincluding cancer, AIDS, and in bone marrow transplantation therapy.

Overview of Oral Mucositis

Oral mucositis is a significant problem in patients receivingchemotherapy or radiation therapy. Estimates of oral mucositis in cancertherapy range from 40% of those receiving standard chemotherapy to 76%of bone marrow transplant patients. Virtually all patients who receiveradiation therapy to the head and neck area develop oral complications.Mucositis is not only painful, but it also can limit adequatenutritional intake and decrease the willingness of patients to continuetreatment. More severe mucositis with extensive ulceration may requirecostly hospitalizations with parenteral nutrition and narcotics.Mucositis diminishes the quality of life and may result in seriousclinical complications. A healthy oral mucosa serves to clearmicroorganisms and provides a chemical barrier that limits penetrationof many compounds into the epithelium. A mucosal surface that is damagedincreases the risk of a secondary infection and may even prove to be anidus for systemic infection. Mucositis may result in the need to reducedosage in subsequent chemotherapy cycles or to delay radiation therapy,which may ultimately affect patient response to therapy.

Normally, cells of the mouth undergo rapid renewal over a 7- to 14-daycycle. Both chemotherapy and radiation therapy interfere with cellularmitosis and reduce the ability of the oral mucosa to regenerate. Cancerchemotherapeutic drugs that produce direct stomatotoxicity include thealkylating agents, antimetabolites, natural products, and othersynthetic agents such as hydroxyurea and procarbazine hydrochloride.Typical sequelae of these cytotoxic agents include epithelialhyperplasia, collagen and glandular degeneration, and epithelialdysplasia. Mucositis is an inevitable side effect of radiation. Theseverity of the mucositis is dependent on the type of ionizingradiation, the volume of irradiated tissue, the dose per day, and thecumulative dose. As the mucositis becomes more severe, pseudo membranesand ulcerations develop. Poor nutritional status further interferes withmucosal regeneration by decreasing cellular migration and renewal.

Direct stomatotoxicity is usually seen 5 to 7 days after theadministration of chemotherapy or radiation therapy. In thenonmyelosuppressed patient, oral lesions heal within 2 to 3 weeks. Theno keratinized mucosa is most affected. The most common sites includethe labial, buccal, and soft palate mucosa, as well as the floor of themouth and the ventral surface of the tongue. Clinically, mucositispresents with multiple complex symptoms. It begins with asymptomaticredness and erythema and progresses through solitary white elevateddesquamative patches that are slightly painful to contact pressure.Following these large, acutely painful contiguous pseudo membranouslesions will develop with associated dysphagia and decreased oralintake. Histopathologically, edema of the retepegs is noted, along withvascular changes that demonstrate a thickening of the tunica intima withconcomitant reduction in the size of the lumen and destruction of theelastic and muscle fibers of the vessel walls. The loss of theepithelial cells to the basement membrane exposes the underlyingconnective tissue stroma with its associated innervation, which, as themucosal lesions enlarge, contributes to increasing pain. Oralinfections, which may be due to bacteria, viruses, or fungal organisms,can further exacerbate the mucositis as well as lead to systemicinfections. If the patient develops both severe mucositis andthrombocytopenia, oral bleeding may occur that is very difficult totreat.

A mucositis grading system gives the physician the ability to assess theseverity of the mucositis in terms of both the pain and the patient'sability to maintain adequate nutrition so that a treatment plan can beappropriately constructed. There are many different grading systems;most are based on two or more clinical parameters, including erythema,pain, and problems with eating. An example of a common grading system isthat proposed by the National Cancer Institute, which uses a numberingscale of 0 to 4. Grade 0 means no mucositis; grade 1, the patient haspainless ulcers, erythema, or mild soreness; grade 2, the patient haspainful erythema, edema, or ulcers but can eat; grade 3, the patient haspainful erythema, edema, or ulcers and cannot eat; and grade 4, thepatient requires parenteral or enteral support.

-   -   (source: DeVita: Cancer: Principles and Practice of Oncology,        5th ed., Copyright© 1997 Lippincott-Raven Publishers)        Current Methods for the Prevention and Treatment for Mucositis

In spite of the significance of the problem, there are currently nowell-established procedures and formulations for the prevention andtreatment of mucositis. As a result, there is no standardized approach,and many institutes have adopted treatment regimens based on little orno supporting data of safety and efficacy. There is even disagreement onwhether good oral hygiene is beneficial (for example: Dodd M J,Miaskowski C, Shiba G H, Dibble S L, Greenspan D, MacPhail L, Paul S M,Larson P, Risk factors for chemotherapy-induced oral mucositis: dentalappliances, oral hygiene, previous oral lesions, and history of smoking,Cancer Invest 1999;17(4):278–84 and Cheng K K, Molassiotis A, Chang A M,Wai W C, Cheung S S. Evaluation of an oral care protocol intervention inthe prevention of chemotherapy-induced oral mucositis in pediatriccancer patients, Eur J Cancer 2001 November;37(16):2056–6). Good oralhygiene is typically recommended, supplemented by formulations which arecompounded locally and primarily used to provide prophylaxis. Thus,patients will be asked to use ice, saline rinses, bicarbonate rinses, orrinse with antimicrobial formulations such as acyclovir orchlorhexidine. (Fulton J S, Middleton G J, McPhail J T, Management oforal complications, Semin Oncol Nurs 2002 February;18(1):28–35).Regimens commonly used for the treatment of mucositis and its associatedpain include a local anesthetic such as lidocaine or Dyclone, Maalox orMylanta, diphenhydramine (Benadryl), nystatin, or sucralfate. Theseagents are either used alone or in different combinations of the abovemedications made into a mouthwash. Other agents used less commonlyinclude Kaopectate, allopurinol, vitamin E, beta-carotene, Kamillosanliquid, aspirin, antiprostaglandins, prostaglandins, silver nitrate, andantibiotics. Oral and sometimes parenteral narcotics are used for painrelief. (DeVita: Cancer: Principles and Practice of Oncology, 5th ed.,Copyright© 1997 Lippincott-Raven Publishers). Recent reviews of currenttreatment options and of investigational clinical trials indicated thatmost agents and options failed to show any benefit in the preventionand/or treatment of mucositis. (Worthington H V, Clarkson J E, Eden O B,Interventions for treating oral mucositis for patients with cancerreceiving treatment, Cochrane Database Syst Rev 2002;(1): CD001973;Demarosi F, Bez C, Carrassi A., Prevention and treatment of chemo- andradiotherapy-induced oral mucositis. Minerva Stomatol 2002May;51(5):173–86).

A recent review (Sonis S T, Fey E G, Oral Complications of CancerTherapy, Oncology 2002, 16:680–695) provides an overview of the manyagents which have been evaluated in clinical studies for the preventionand treatment of mucositis, and concludes “there is no effectiveapproved treatment for mucositis”, and that there is no conclusiveevidence that experimental agents which are currently the subjects ofclinical studies will provide benefit to future patients. While ongoingstudies are providing a better understanding of the etiology ofmucositis, it may be some time before this knowledge can be translatedinto effective new treatments. In the meantime, the main approaches arebased upon theory, and it is anticipated that it may be many yearsbefore rationale drug design can be applied based upon a betterunderstanding of etiology.

The current approaches can be classified as “palliative, cytoprotective,anti-inflammatory, and antimicrobial agents, and cytokines” (Plevova P:Prevention and treatment of chemotherapy- and radiotherapy-induced oralmucositis: A review. Oral Oncol 35:453–470, 1999; Sonis S T, Fey E G,Oral Complications of Cancer Therapy, Oncology 2002, 16:680–695).

Examples of each type are:

-   i) Palliative: saline and bicarbonate rinses, sucralfate    suspensions, and topical analgesics (for example, viscous lidocaine,    dyclonine, diphenhydramine, and loperamide.-   ii) Cytoprotective: Ice chips, allopurinol, glutamine,    pentoxifylline, Ethyol, and antioxidants such as vitamins C and E.-   iii) Anti-inflammatories: Benzydamine, indomethacin, and amlexanox.-   iv) Anti-microbials: chlorhexidine, povidone iodine, the protegrin    IB-367.-   v) Cytokines: Keratinocyte growth factor, transforming growth    factor-beta 3, and interleukin-11, and the colony-stimulating    factors: G-CSF and GM-CSF.

Topical coating agents such as magnesium hydroxide (e.g., Milk ofMagnesia), Kaopectate (Pharmacia & Upjohn, Columbus, Ohio), OraRinse(Carrington Laboratories), GelClair (Sinclair Pharmaceuticals) andaluminum hydroxide gel (Amphojel; Wyeth-Ayerst, Philadelphia, Pa.) mayprovide some symptomatic relief of the lesions associated with mucositis(J B Epstein, A W Chow, Oral complications associated withimmunosuppression and cancer therapies, Infectious Disease Clinics ofNorth America, 1999, 13(4), 901–923).

While palliation provides temporary relief, none of the above treatmentsprovides any proven benefit in preventing or treating mucocitis, withthe possible exception of the use of ice chips during 5-FU therapy.Therefore, the development of a product which provides clinically provenbenefit for the prevention and/or treatment of mucositis remain a majorunmet medical need.

SUMMARY OF THE INVENTION

It is an aim of the present invention to provide viscous, mucoadhesiveliquid and mucoadhesive gel formulations to be used for the preventionand treatment of mucocutaneous disorders. The formulation may be usedwith or without one or more active pharmaceutical agents. Theseformulations are especially beneficial in diseases and conditions inwhich a wide area of the mucosal surface requires treatment, but theformulations may also be used in treating small areas of the mucosalsurface.

In order that mucocutaneous disorders are treated effectively, it ispreferred that the lesion is in contact with the liquid or gel,mucoadhesive formulation for the period of time required to derivebenefit. To grant such benefit, this invention describes mucoadhesive,viscous liquid and mucoadhesive gel formulations which may or may notcontain one or more pharmaceutically active ingredients. The liquid canreadily be applied to the affected region of the mucosa by methods knownin the art, while the high viscosity and mucoadhesion will cause liquidor gel to remain in contact with the lesion for extended periods. Theformulations of the present invention may be applied to treatmucocutaneous lesions in a variety of body compartments, including, butnot limited to, the oral cavity, the nasal cavity, the esophagus, therectum, the bladder, and the vagina.

The present invention involves a composition for the treatment andprevention of mucocutaneous disorders. This composition of the presentinvention, in one embodiment, comprises an amount of a mucoadhesiveeffective to coat the mucocutaneous area being treated and also atherapeutically or prophylactically active drug for a mucocutaneousdisorder. In an important embodiment, the mucoadhesive is at aviscosity-inducing concentration. In another embodiment of the presentinvention, the mucosal drug delivery composition useable in thetreatment or prevention of a mucocutaneous disorder is described. Thiscomposition comprises an amount of a mucoadhesive to form an effectivecoat in the mucocutaneous area being treated, a viscosity-inducing agentand a therapeutic or prophylactic drug for mucocutaneous disorders. Themucoadhesive of the present invention in one embodiment may be a naturalor synthetic linear or cross linked polymer. This mucoadhesive can befor example a linear or cross-linked polyacrylic acid,carboxymethylcellulose, hydroxyalkylcellulose, polyvinylpyrrolidonedextran sulfate, dermatan sulfate, a water-soluble vinyl polymer, guargum, xanthan gum tragacanth gum and pectin or chitosan. In thecomposition of the present invention a mucoadhesive is generally at aconcentration between about 0.1 w/w % and about 3.0 w/w %. In preferredembodiments, the mucoadhesive of the present invention will containcross-linked polyacrylic acid hydrogels plus optional linearpolyacrylate and/or polymethacrylate and/or linear copolymers derivedfrom acrylate and methacrylate monomers. Useable viscosity-inducingagents are many and include agar, bentonite, glycerin, providone,kaolin, tragacanth, sodium alginate and cross-linked polyacrylic acids.The composition of the present invention is preferably at a pH betweenabout 6.5 and about 9.5.

Among the mucocutaneous disorders treatable by their methods andcompositions of the present invention are: mucositis, Bechet's disease,apthous ulcer, bullous pemphigoid, chemical cystitis, radiationcystitis, erythema multiforme, esophagitis, interstitial cystitis, oralLichen planus, pemphigus, radiation proctitis, or ulcerative colitis.

An important aspect to the present invention involves a method for theprevention or treatment of mucocutaneous disorders. This method involvesidentifying a patient having or possibly developing a mucocutaneousdisorder. Next in this method is the administration to the patient of aformulation comprising a mucoadhesive agent in an amount effective toprevent or treat the mucocutaneous disorder. Of course, this formulationmay and often does include a viscosity-inducing agent and/or aviscosity-enhancing concentration of mucoadhesive. Mucocutaneousdisorders treatable by this method are described above. The liquidformulation of this invention are often more useful when possessingpseudoplastic behavior, which provides for reduced viscosity duringapplication, allowing the liquid to cover the mucosa more readily, andfor increased viscosity of the liquid when in place on a mucocutaneousarea. In terms of the length of treatment, this will vary according tothe severity and type of disorder. It is expected that the alleviationof mucocutaneous disorders should be visible to anyone treating thepatient and that the method of treatment should continue until recoveryis clear. This may take from hours to days to weeks, depending upon thesituation. Preferred mucoadhesive agents for this method are describedabove. Likewise, for viscosity-inducing agents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 1 a show an in vitro model developed to demonstrate theenhanced delivery of active pharmaceutical ingredients to the surface ofmucosal membrances.

FIG. 2 shows the device described in FIG. 1 is attached to LC pumps 2–3using 10/31″ ferules and large diameter HPLC tubing.

FIGS. 3 and 3 a show results of amlexanox delivery of three differenceformulations when tested using the device shown in FIGS. 1 and 2.

FIG. 4 summarizes the result of a comparison of the formulationsdescribed in Example 7.

FIG. 5 shows the rheological behavior as measured in Example 8.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention describes formulations for the prevention andtreatment of disorders of mucous membranes in humans and animals. Theliquid or gel formulations of the present invention are ideally suitedto treat diseases and disorders which affect a wide area of the mucosalsurface, but they also provide the opportunity to treat discrete,localized lesions, especially in the oral cavity. The mucous membraneswhich may be treated by the compositions described in this patentinclude, but are not limited to, those in the oral cavity, the nasalcavity, the gastrointestinal and respiratory tracts, the vagina, and thebladder. Inflammatory, erosive, and/or ulcerative diseases which can betreated by topical application of the compositions described in thispatent include, but are not limited to, aphthous ulcers, Behgetsyndrome, bullous pemphigoid, chemical or radiation-induced cystitis,erythema multiforme, esophagitis, interstitial cystitis, mucositis, orallichen planus, pemphigus, and radiation proctitis. In conditions such asaphthous ulcers, chemical or radiation-induced cystitis, mucositis, andradiation proctitis, when the onset of the inflammatory, erosive, and/orulcerative condition may be forecast (for example, by prodromalsensations in the case of aphthous ulcers, and by initiation ofchemotherapy and/or radiation therapy in the treatment of cancer), thecompositions of this invention might be applied prior to the formationof lesions, or at the commencement of therapy to prevent or delay theonset of inflammatory, erosive, and/or ulcerative lesions. While amucoprotective agent may be a mucoadhesive alone, a viscous mucoadhesiveliquid or mucoadhesive gel arepreferred particularly when apharmaceutical agent is present to be selectively transmitted to amucosal target.

As described later in the Examples section, one of the viscous,mucoadhesive formulations of the current invention, a viscous liquidwhich is composed entirely of pharmaceutically-accepted excipients,demonstrated a surprising result in a clinical study. This studyexamined the degree of mucositis in patients receiving radiotherapy forhead and neck cancer. The mean and median mucositis scores for patientsrinsing six times a day with one of the viscous, mucoadhesive solutionsof the current invention for the duration of radiation therapy (6–7weeks), with or without concombinant chemotherapy, were much lower thanthe scores for patients who did not use this rinse.

Furthermore, mucoadhesive liquid/gel formulations of the currentinvention which are also composed entirely of pharmaceutically-acceptedexcipients, demonstrated a surprising results in a hamster model ofradiation induced mucositis.

There is currently no complete explanation of why the viscous,mucoadhesive liquids and gels of the current invention without a knownactive pharmaceutical ingredient should provide such benefit topatients. The following are considered viable possibilities, but thisinvention should not be considered as limited to any one of thesepossibilities:

A viscous, mucoadhesive solutions provides a layer on the surface of themucosa for an extended period, and this may have a beneficial effect,for example, a moisturizing or barrier effect, so limiting the damage tothe mucosal surface caused by disease, or injury from ionizing radiationand/or chemotherapeutic agents. Thus, it is envisioned that any aqueousformulation which is formulated with non-toxic and non-irritatingexcipients and providing a liquid or gel-which is both viscous andmucoadhesive might be expected to provide benefit to patients sufferinga disease or disorder of the mucosa.

It is known that polyanionic carbohydrate polymers and oligomers canhave a beneficial effect in the treatment of mucosal disorders. Forexample, pentosan polysulfate and hyaluronic acid are known to providebenefit to patients with interstital cystitis (Morales A, et al,Treatment of refractory interstitial cystitis, Int Urogynecol J PelvicFloor Dysfunct 1996;7(4):215–20). It is quite possible that otherpolyanionic and polycationic compounds, whether carbohydrate, of naturalorigin or synthetic, may also provide benefit in the prevention andtreatment of mucosal disorders. Linear and partially cross-linkedpolyanionic polymers are included in the formulation used in the productdemonstrating benefit in the mucositis clinical study described in theexamples.

Other components of the formulation used in the clinical study, benzylalcohol, citric acid, glycerin, polysorbate 60, and saccharin, alone orin combination with each other and/or the other excipients of theformulation may have a beneficial effect. Other preservatives,humectants, emulsifying agents, antioxidants, antimicrobial agents,solubilizing agents, and other excipients known in the art in theformulation of liquid pharmaceutical products, alone or in combination,may also provide for, or enhance, the beneficial properties on mucosalsurfaces, when formulated to provide a viscous, mucoadhesive solution.

Other components of the liquid/gel formulations used in the hamstermodel of mucositis (phenoxyethanol, glycine, glycerol, ethanol) alone orin combination with each other and/or the other excipients of theformulation may have a beneficial effect. Other preservatives,humectants, emulsifying agents, antioxidants, antimicrobial agents,solubilizing agents, and other excipients known in the art in theformulation of gel pharmaceutical products, alone or in combination, mayalso provide for, or enhance, the beneficial properties on mucosalsurfaces, when formulated to provide a mucoadhesive gel.

Viscous, mucoadhesive formulations for the prevention and treatment ofmucosal diseases and disorders may additionally be formulated with oneor more compounds known to be pharmaceutically active. Addition offurther pharmaceutically active compounds could provide greater benefitto patients in the prevention and treatment of mucosal disorders.Examples of pharmaceutically active compounds which could beincorporated in the viscous, mucoadhesive solutions of this invention asprovided later in this section.

Aqueous solutions of pharmaceutically-active compounds are well known inthe art as convenient drug delivery formulations. Such formulations aremost useful for oral delivery, when the solution is swallowed, and thedrug is presented to the stomach and gastrointestinal tract in a formwhich is amenable to rapid absorption. Aqueous solutions are also usedto deliver drugs to mucosal tissue. In general, aqueous solutions usedto deliver pharmaceuticals tend to be non-viscous and non-mucoadhesive.For oral delivery, this property is undesirable, as it minimizes theamount of drug which is retained in the oral cavity and esophagus, whilemaximizing that delivered to the stomach and gastrointestinal tract. Onepreferred drug for the treatment of mucocutaneous disorders isamlexanox.

For topical treatment of mucosal membranes, aqueous solutions ofpharmaceutically-active compounds offer the advantage over other dosageforms in that a wide area of the mucosa can be readily covered with thesolution, which is of benefit if the area to be treated is not a single,discrete region. Also, mucosa not readily accessible can be treatedusing aqueous solutions of pharmaceutically-active compounds and simplemethods of application. However, formulations which are non-mucoadhesiveand non-viscous are less than ideal for delivery of drugs to mucosalsurfaces. Such solutions will be rapidly removed from the area beingtreated, for example, because the liquid flows from the site ofapplication under the influence of gravity, and/or because the naturalsecretions of mucosal membranes carry the solution from the site ofapplication.

The present invention involves a finding that neither high viscosity normucoadhesion alone confers ideal properties. A viscous butnon-mucoadhesive liquid will not be held in place on the mucosalsurface. Instead, a non-mucoadhesive solution will readily be lost fromthe point of application, for example, under the influence of gravity,and/or through natural movements of the membrane and surroundingstructures, and/or the flow of natural secretions. In an aqueous liquidformulation which is mucoadhesive but has low viscosity, only a thinlayer of the liquid which is adjacent to the mucosa may be held inplace, but the bulk of the liquid might rapidly flow from the site ofapplication under the influence of gravity and/or be readily removed bythe natural secretions of mucosal membranes. In a mucoadhesive, viscousliquid formulation, the liquid will adhere to the mucosa, while the highviscosity of the liquid will reduce the rate of removal of the bulk ofthe liquid from the site of application. In some cases a low viscositymucoadhesive may provide effective treatment, especially whenpharmaceutical agents are not required. A mucoadhesive agent may itselfbe a viscosity-inducer and thus serve two purposes. The term“viscosity-inducing” is meant to mean enhancement of the aqueousmucoadhesive layer that adheres to mucosal areas.

For most liquids, viscosity remains constant over a wide range of shearrates. This phenomenon is known as Newtonian viscosity, and liquidswhich display this property are called Newtonian liquids. Liquids inwhich viscosity varies with shear rate are termed non-Newtonian. Thereare several known non-Newtonian profiles. One of these profiles istermed pseudoplastic, and liquids which fall into this categorydemonstrate a decrease in viscosity as shear rate increases. Preferredformulations of the current invention are pseudoplastic, and demonstratea decrease in viscosity at low shear rates. Pseudoplasticity benefitsthe application of the formulations of the current invention by virtueof the fact that application of shear (for example, swishing the liquidin the mouth) reduces the viscosity, so allowing the liquid to flow andcoat the mucoscal surface more readily. Once the shear forces arediscontinued, the viscosity of the liquid increases, as required (incombination with mucoadhesion) for prolonged attachment to the mucosalsurface.

Formulations of the current invention are viscous, free-flowing liquidsor mobile gels that are either Newtonian or pseudoplastic. The abilityto flow freely or be spread freely is advantageous in order to readilycoat either a selected region or a wide area of the affected mucosalmembrane, and to coat mucosal membranes not readily accessible to simpleapplication. The solutions of the current invention will haveviscosities at zero shear in the range 100–20,000 cP.

The stable, viscous, mucoadhesive liquid formulations of the presentinvention may be applied to mucosal membranes for the delivery ofpharmaceutically active compounds to the mucosal membranes forprevention and/or treatment of disorders or diseases of these membranes.The liquid may be applied, e.g., to the following mucosal surfaces; theoral cavity, the nasal cavity, the gastrointestinal and respiratorytracts, the vagina, and/or the bladder. The formulations of the currentinvention may also be applied to other mucous membranes for theprevention and treatment of disorders and diseases. Many methods knownin the art for the delivery of liquids to body compartments may be used.

For treatment of disorders and diseases of the oral cavity, the stable,viscous, mucoadhesive liquid formulations of the current invention maybe taken by mouth and distributed throughout the oral cavity by aswishing action, or by the patient adopting a slow circulating movementof the head. Excess solution can either be swallowed or expelled. Fortreatment of disorders and diseases of the oral cavity, the stable,mucoadhesive gel formulations of the current invention may be taken bymouth and distributed throughout the oral cavity by the action of thetongue and/or use of a swab or similar device. Excess gel can either beswallowed or expelled.

For treatment of disorders and diseases of the esophagus, the stablemucoadhesive liquid and gel formulations of the current invention can beswallowed with minimal contact of the oral cavity, or administered bygavage, or by spraying the liquid into the throat.

For treatment of disorders and diseases of the nasal cavity, the stablemucoadhesive liquid and gel formulations of the current invention can bedelivered as droplets or by spraying the liquid into the nose.

For treatment of disorders and diseases of the bladder, the stable,mucoadhesive liquid or gel formulations of the current invention can bedelivered by intravesical administration.

For treatment of disorders and diseases of the rectum and lowergastrointestinal tract, the stable mucoadhesive liquid or gelformulations of the current invention can be administered by catheter orenema.

Other methods to apply the stable, viscous, mucoadhesive liquidformulations and stable mucoadhesive gel formulations of the currentinvention to mucosal tissues are known to those skilled in the art.

Pharmaceutically active compounds which may be formulated with thestable mucoadhesive liquid and gel formulations of the current inventionfor topical treatment of a mucosa can include, either alone or incombination, one or more of the following classes of drugs: anti-allergycompounds, anti-inflammatory analgesic agents, steroidal andnon-steroidal anti-inflammatory agents, antioxidant compounds,analgesics, antihistamines, local anesthetics, bactericides anddisinfectants, vasoconstrictors, hemostatics, antibiotics, keratolytics,cauterizing agents, antiviral drugs, growth factors, supplements andother potential agents for treatment of mucositis. Other classes ofpharmaceutically active agents may also be formulated with the stablemucoadhesive liquid and gel formulations of the current invention.

Examples of anti-inflammatory analgesic agents include acetaminophen,methyl salicylate, monoglycol salicylate, aspirin, mefenamic acid,flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenacsodium, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen,sulindac, fenclofenac, clidanac, flurbiprofen, fentiazac, bufexarnac,piroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine,mepirizole, tiaramide hydrochloride, etc.

Examples of steroidal anti-inflammatory agents include hydrocortisone,predonisolone, dexamethasone, triamcinolone acetonide, fluocinoloneacetonide, hydrocortisone acetate, predonisolone acetate,methylpredonisolone, dexamethasone acetate, betamethasone, betamethasonevalerate, flumetasone, fluorometholone, beclomethasone diproprionate,etc.

Examples of antioxidant compounds include ascorbic acid, dehydroascorbicacid, alpha-tocopherol, glutathione, beta-carotene, azelastine,N-acetyl-L-cysteine, allopurinol, flavanoids, etc.

Examples of antihistamines include diphenhydramine hydrochloride,diphenhydramine salicylate, diphenhydramine, chlorpheniraminehydrochloride, chlorpheniramine maleate isothipendyl hydrochloride,tripelennamine hydrochloride, promethazine hydrochloride, methdilazinehydrochloride, etc.

Examples of local anesthetics include dibucaine hydrochloride,dibucaine, lidocaine hydrochloride, lidocaine, benzocaine,p-buthylaminobenzoic acid 2-(di-ethylamino) ethyl ester hydrochloride,procaine hydrochloride, tetracaine, tetracaine hydrochloride,chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine,cocaine hydrochloride, piperocaine hydrochloride, dyclonine, dycloninehydrochloride, etc.

Examples of bactericides and disinfectants include phenoxyethanol.triclosan, thimerosal, phenol, thymol, benzalkonium chloride,benzethonium chloride, chlorhexidine, povidone iodide, cetylpyridiniumchloride, eugenol, trimethylammonium bromide, etc.

Examples of vasoconstrictors include naphazoline nitrate,tetrahydrazoline hydrochloride, oxymetazoline hydrochloride,phenylephrine hydrochloride, tramazoline hydrochloride, etc.

Examples of hemostatics include thrombin, phytonadione, protaminesulfate, aminocaproic acid, tranexamic acid, carbazochrome,carbaxochrome sodium sulfanate, rutin, hesperidin, etc.

Examples of antibiotics include penicillin, meticillin, oxacillin,cefalotin, cefalordin, erythromcycin, lincomycin, tetracycline,chlortetracycline, oxytetracycline, metacycline, chloramphenicol,kanamycin, streptomycin, gentamicin, bacitracin, cycloserine, andclindamycin.

Examples of keratolytics include salicylic acid, podophyllum resin,podolifox, and cantharidin. Examples of cauterizing agents include thechloroacetic acids and silver nitrate.

Examples of antiviral drugs include protease inhibitors, thymidinekinase inhibitors, sugar or glycoprotein synthesis inhibitors,structural protein synthesis inhibitors, attachment and adsorptioninhibitors, and nucleoside analogues such as acyclovir, penciclovir,valacyclovir, and ganciclovir.

Examples of anti-allergy compounds include alopatadine, astemizole,cromolyn, fenpiprane, repirinast, tranilast, traxanox, etc.

Examples of growth factors, supplements and other potential agents fortreatment of mucositis includes keratinocyte growth factor,granulocyte-colony-stimulating factor, transforming growth factor-beta3,sucralfate, L-glutamine, aminoacids, lisofylline, IL-15, antimicrobialpeptides and histamine.

The amount of pharmaceutically active compound(s) to be used depends onthe desired treatment strength, although preferably, the pharmaceuticalcomponent comprises 0.001 to 30% by weight of the formulation, and morepreferably between 0.005 and 20% by weight.

In addition to the preferred requirements of mucoadhesion and viscosityas described above, it is important, for use of the formulation for theprevention and treatment of mucosal diseases and disorders that theliquid or gel be stable, such that it can be stored at ambienttemperatures for many months or years, even when subjected to briefperiods of elevated or depressed temperatures, without physical orchemical degradation of the formulation. It is usually desirable toformulate the product without use of any organic solvents, the presenceof which might irritate the mucosal lesions being treated, althoughliquid and gel formulations containing pharmaceutically-acceptableorganic solvents are within the scope of this invention provided thatthe incorporation of such solvents does no harm to the mucosa, andpossibly provides benefit; for example, as disinfectants, or to aid thesolvation of the mucous membrane to provide more rapid mucoadhesion, orfor concentration of the excipients (through evaporation of the solventfollowing application to the mucosa) to enhance mucoadhesion and/orviscosity following application. Furthermore, it is desirable toformulate the viscous, mucoadhesive solution using only excipients whichare accepted by all major pharmaceutical regulating authorities as safe.

The following list provides examples of components of the stable,viscous, mucoadhesive formulations of the current invention:

A linear or cross-linked polymer polyanionic or polycationic polymerwhich may or may not already be known to provide mucoadhesion. Suchpolymers include (but are not limited to) linear polyacrylic acid, across-linked homopolymer based on acrylic acid, a crosslinked copolymerbased on acrylic acid, linear methacrylic acid homopolymers andcopolymers, carboxymethylcellulose, hydroxyalkylcellulose, dextransulfate, dermatan sulfate, and hyaluronic acid. Other mucoadhesivepolymers are well-known to those skilled in the art. The mucoadhesiveformulations of the current invention can contain a single mucoadhesivecomponent, or mixtures thereof. The preferred mucoadhesive polymers arecross-linked homopolymers and copolymers based on acrylic acid andmethacrylic acid, especially the Carbopol and polycarbophil polymerssupplied by B.F. Goodrich, and Eudragit polymers supplied by Rohm-Haas;most preferred are Carbopol™, (polymer of acrylic acid cross-linked withpolyalkenyl ethers or divinyl glycol) Noveon AA1®, (also calledpolycarbophil, a salt of polyacrylic acid cross-linked with polyether ordivinyl glycol) and Eudragit L-100 (methacrylic acid-ethyl acrylatecopolymer (1:1)).

Viscosity enhancement is provided by one or more of the above mentionedmucoadhesive polymers alone or in combination with agar, bentonite,glycerin, povidone, kaolin, and/or tragacanth and sodium alginate. Mostpreferred is Carbopol in combination with glycerin.

The pH of the solution is adjusted to the final desired pH with anypharmaceutically accepted acid or base. Most preferred is sodium orpotassium hydroxide, phosphoric acid, or citric acid. A final pH of 6.5to 9.5 is preferred.

To prevent microbial growth in the formulation during storage, it isdesirable to include a preservative. Preservatives known in the artinclude benzyl alcohol, benzoate salts, phenoxyethanol, methylparaben,and propylparaben. Phenoxyethanol and benzyl alcohol are the mostpreferred preservatives.

A humectant is desirable to provide a pleasant mouth-feel in oralapplications. Humectants known in the art include cholesterol, fattyacids, glycerin, lauric Acid, magnesium stearate, pentaerythritol, andpropylene glycol. Glycerin is preferred.

An emulsifying agent might be necessary, for example to ensure completedissolution of all excipients, especially hydrophobic components such asbenzyl alcohol. Many emulsifiers are known in the art. The preferredemulsifier is polysorbate 60

For oral applications, it may be desirable to add a pharmaceuticallyacceptable flavoring agent, coloring agent and/or sweetener. Compoundssuch as saccharin, glycerin, simple syrup, and sorbitol are useful amongthose as sweeteners. Saccharin is preferred.

It may be desirable to include other ingredients; for example apharmaceutically acceptable organic solvent, a buffering agent, anantioxidant, a free radical scavenger, an antimicrobial agent, and/or acoloring agent. The exact formulation of the above ingredients, and themethod of manufacture, will be apparent to those skilled in the art. Anumber of texts provide assistance in the design and manufacture ofpharmaceutical formulations, including Remington's PharmaceuticalSciences, Mack Publishing Company Co., Easton, Pa., and Pharmaceuticaldosage forms and drug delivery, Ansel et al, 1995, Williams and Wilkins,Malvern, Pa.

The following examples are provided to demonstrate the beneficialeffects of stable mucoadhesive liquids and gels of this invention.Example 4 is provided to demonstrate that both mucoadhesion andviscosity are desired to provide the coating of a liquid on anartificial mucosal surface with extended retention properties. In thisin-vitro model of the mucosal surface, a steady flow of artificialsaliva across the ‘mucosal’ surface attempts to remove the liquidcoating. The hydrophobic drug amlexanox is used as a marker of filmerosion and retention (the latter by delivery of the marker across themodel mucous membrane). The study clearly demonstrates that the liquidrequires both mucoadhesion and viscosity for retention.

Example 6 presents an analysis of a clinical study of a stable, viscous,mucoadhesive rinse formulation of this invention compared with standardcare in patients receiving radiation therapy to the head and neck. Thisanalysis provided the surprising result that the stable, viscous,mucoadhesive rinse formulation of this invention, without an acceptedpharmaceutically active ingredient, lowered the mean and medianmucositis scores of these patients when compared to a similar group ofpatients receiving standard care for mucositis.

Example 8 presents the results of a study in Syrian hamsters in whichmucositis is induced by irradiation of the oral cavity. Six gelformulations were tested in this model, and the severity of mucositisfor each treatment group is expressed as the mean number of days thatthe animals in each group experienced a mucositis score of three ormore. A score of three represents the onset of ulceration, and a higherscore represents greater severity of mucositis. The formulations testedin this study are listed in example 7. None of the formulations containan accepted pharmaceutically-active ingredient. The results of thisstudy clearly demonstrate the following:

a. The most effective formulation (A and B) contains a mixture of twomucoadhesive polymers; Carbopol 971 and Noveon AA1.

b. Across the series, there is a trend that effectiveness generallyincreases with viscosity, providing evidence of the importance ofviscosity of liquid and gel formulations used to treat mucositis.

c. Formulation B (which is the same as A, except that Eudragit L-100 iseliminated) has similar, but slightly reduced efficacy as compared to A;the small difference observed is not statistically significant, andcould be explained by viscosity.

d. Formulation C results from elimination of phenoxyethanol fromformulation B. Phenoxyethanol is a preservative with known antisepticand bactericide properties. While formulation C is clearly effective inreducing the severity of mucositis, the formulation is clearly moreeffective when the antiseptic/bactericide is present.

e. Formulation D is the same as B, except that glycine buffer isreplaced by borate buffer. The viscosity of formulation D is marginallylower than that of B, which may account for some of the difference, butthe data also indicates that there is a benefit provided by theaminoacid.

f. Formulation E is the same as B, except that Noveon AA1 is eliminated.Viscosity and mucoadhesion are provided only by Carbopol 971. The totalconcentration of cross-linked acrylate has to be increased to provide asimilar viscosity. The poor efficacy of this formulation may be largelydue to its reduced viscosity.

g. Formulation F is the same as B except that all of the mucoadhesivepolymers are replaced by non-mucoadhesive polymeric thickening agents.The viscosity of this formulation is slightly higher than B, yet it hasno efficacy (as compared with saline), demonstrating the importance ofmucoadhesion as well as viscosity to efficacy.

EXAMPLES Example 1 Preparation of Viscous, Mucoadhesive AqueousComposition

A viscous, mucoadhesive aqueous solution was formulated by addingCarbopol® 971P NF to water using an appropriate mixing apparatus (MasterServodyne® mixer with high-lift blade rotating at 200–300 rpm) to give aclear solution. An aqueous solution of potassium hydroxide was addedwith stirring to give a clear gel. An aqueous solution of potassiumhydroxide, citric acid, saccharin sodium, phosphoric acid and glycerinwas added with stirring to give a clear solution. A solution of benzylalcohol and polysorbate 60 was added with stirring to give a clearsolution. The pH was adjusted to 7.0–7.8 with an aqueous solution ofphosphoric acid. The resulting product was mixed further for 30 minutes.

The formulation of the product is set out in Table 1:

TABLE 1 Ingredients Weight Percent purified water 90.68  10% potassiumhydroxide c.a. 4.6 benzyl alcohol 1.50 polysorbate 60 0.05 Carbopol ®971P 0.35 0.5% phosphoric acid c.a. 5.7 citric acid 0.05 saccharinsodium 0.40 glycerin 5.00 Natural orange flavor 0.05

Example 2 Preparation of Viscous, Mucoadhesive Aqueous CompositionContaining Amlexanox

The method set out in example one was followed to provide a viscous,mucoadhesive aqueous composition of the following formula:

TABLE 2 Ingredients Weight Percent purified water 91.21  potassiumhydroxide 0.60 benzyl alcohol 1.50 polysorbate 60 0.05 Carbopol ® 971P0.35 phosphoric acid 0.13 citric acid 0.05 saccharin sodium 0.40amlexanox 0.50 glycerin 5.20

Example 3 High Performance Liquid Chromatographic Assay for theAmlexanox

The following HPLC parameters were employed in performing an assayingfor amlexanox:

-   Phenomenex, Prodigy, 5 μm ODS (2), 150 mm×4.6 mm-   Mobile Phase: 25% THF/75% 10 mM phosphate buffer, pH 8.0    -   h. Flow Rate: 1.0 mL/min-   Injection Volume: 10 μL    -   i. Detector: UV@ 244 nm

Example 4 Demonstration of Drug Delivery From Liquid Formulations in anin vitro Model of a Mucosal Surface

Referring to FIG. 2, the device described in FIG. 1 is attached to LCpumps 2–3 using 10/32″ ferules and large diameter HPLC tubing. One halfof the polycarbonate block 7 has a reservoir 1 that provides acontinuous flow of artificial saliva across the Spectra/Por4 dialysismembrane 6 and is eluted into 10 mL vessel 8. The opposing half of thepolycarbonate block 7 is connected to a LC pump 3 which has a reservoir4 of artificial saliva that constantly recirculates across the dialysismembrane 6.

In separate experiments, the composition of example 1 was compared withtwo aqueous formulations of amlexanox which were mucoadhesive butnon-viscous, and viscous but non-mucoadhesive, to demonstrate that bothproperties are required for optimal drug delivery from a free-flowingliquid formulation.

2.9–3.1 mL of the aqueous formulation of amlexanox is applied to thedialysis membrane of the in vitro system, and the flow of artificalsaliva was initiated at a rate of 1.0 mL/min. mL samples were withdrawnfrom the reservoirs 4 and 6 and samples were assayed for amlexanoxcontent using the HPLC assay described in Example 3.

The results of this study are shown in FIG. 3. As can be seen in FIG. 3a, much less amlexanox is washed away in the simulation of saliva flowin the case of the viscous, mucoadhesive solution which is the subjectof this invention compared with the other two formulations. As a result,much more amlexanox (the data indicates a ten-fold difference) isdelivered to the membrane and transported to the receiver vessel in thecase of the viscous, mucoadhesive solution which is the subject of thisinvention compared with the other two formulations.

Example 5 Stability Study

The composition of example 2 was subjected to a stability study. Theclear solution was packaged in clear glass bottles which were sealedwith white screw caps fitted with teflon liners. The bottles weredivided into two groups. One group was stored in a stabilty chamber setat 25° C./60% relative humidity, while the second group was stored at40° C./75% relative humidity. Bottles were examined at 0, 1, 2, 3, and 6months for physical appearance (clarity of the solution), packageintegrity, amlexanox and benzyl alcohol contents, pH, and viscosity. Atall times and under both conditions, no physical or chemical changeswere noted.

Example 6 Clinical Study

A clinical study was conducted in patients 18 years of age or older witha histologically documented diagnosis of head-and-neck cancer and a KPSof at least 60%, who received a radiation dose of at least 60 Gy over6–7 weeks with radiation fields to include at least 40% of the oralmucosa. Patients receiving concomitant chemotherapy were also includedin the study. The patients rinsed using the solution exemplified inexample 1 for 6 times a day (5 mL each time) for the duration of theradiation treatment (6–7 weeks), beginning on the first day of radiationtherapy. An objective measurement of the degree of mucositis (the “SonisScale”, described in Cancer, 1999, 85(10) 2103–13) was made three timesa week for the duration of the study. The following table demonstratesthe mean and median scores of patients on days 14, 28, and 39. Thesedata were obtained on 12 subjects. Historical data (Sonis scalemucositis scores for a similar patient population, 17 patients in total,undergoing similar treatment for head-and-neck cancer) are provided forcomparison.

TABLE 3 Day Day Day 14 28 39 Median No Treatment 0.88 1.50 1.70 Rinse0.87 0.44 0.39 (example 1) Mean No Treatment 1.01 1.50 1.62 Rinse 0.440.81 0.85 (example 1)

Example 7 Mucoadhesive Gel Formulations

Six gel formulations were prepared similarly using a lightning mixerwith an A-100 propeller. For the sample denoted as B detailed below, 354grams of 50 mM glycine/sodium hydroxide buffer solution were added to a600 ml beaker and stirred at 200 rpm. The buffer was prepared bycombining 1 liter of a 0.2 M aqueous glycine solution with 176 ml of 0.2N sodium hydroxide solution and 2984 ml deionized water. Fifty grams of95% USP Ethanol were added next, then 5 grams of glycerin. The stirringspeed was increased to 300 rpm, and 5 grams of Noveon AA1 were addedslowly to the vortex, and the speed gradually increased to 700 rpm. Thissolution was homogenized for one hour. Fifty grams of Carbopol® 971P NFwere added slowly to the vortex and the speed gradually increased to1200 rpm. The material was mixed for an additional one half hour, and 75grams of 2N sodium hydroxide and 5 grams of phenoxyethanol were thenadded. The resulting gel was mixed for an additional one half hour andthe pH measured and found to be 9.82. The mixing speed was reduced to1000 rpm and the pH adjusted to 9.01 using 6.4 ml of 1N hydrochloricacid. The final gel product was clear, homogeneous and transferred to apolypropylene container.

Example 8. Rheology study

A Brookfield viscometer was used to determine the rheological behaviorof the oral rinse at 37±1° C. A rheogram was generated by progressivelyincreasing RPM, from 0.3 up to 60 RPM (upcurve) recording the % Torqueafter each reading stabilized. The upcurve was immediately followed by adowncurve, from 60 RPM to 0.3 RPM. Viscosity is calculated at each RMP,and the stress is then determined by multiplying the viscosity by theRPM. The rheological profile was generated by plotting stress (e.g.,F/A) on the x-axis and the RPM (e.g., Rate of Shear) on the y-axis, andthis result is presented in FIG. 5.

The rinse is clearly pseudoplastic, yet it does not present anyhysteresis. This shear-thinning system has an apparent viscosity thatexceeds 10,000 cP at the lowest rate of shear, but that falls toapproximately 322 cP at 60 RPM, the highest rate of shear employed.

The above method was used to prepare gels with the followingformulations:

TABLE 4 A B C D E F 50 mM 71.5% 70.8% 71.8% 0.0% 67.0% 77.9%Glycine/NaOH Buffer 100 mM 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% Glycine/NaOHBuffer Boric Acid 0.0% 0.0% 0.0% 70.8% 0.0% 0.0% Glycerin 1.0% 1.0% 1.0%1.0% 1.0% 0.9% Noveon AA1 1.0% 1.0% 1.0% 1.0% 0.0% 0.0% Carbomer 1.0%1.0% 1.0% 1.0% 3.0% 0.0% 971-P Eudragit L100 0.1% 0.0% 0.0% 0.0% 0.0%0.0% Ethanol 10.0% 10.0% 10.0% 10.0% 10.0% 9.1% 2N NaOH 14.4% 15.2%15.2% 15.2% 18.0% 0.0% Phenoxy 1.0% 1.0% 0.0% 1.0% 1.0% 0.9% EthanolPolyvinyl 0.0% 0.0% 0.0% 0.0% 0.0% 10.9% Alcohol PEG-20,000 0.0% 0.0%0.0% 0.0% 0.0% 0.3% Totals 100% 100% 100% 100% 100% 100% PH 8.8 9.019.00 9.00 9.00 9.01 Viscosity (cP) 8800 8200 9200 7900 6900 8400 at18.3° C. Total 2.1% 2.0% 2.0% 2.0% 3.0% 0.0% mucoadhesive gel %

Example 9 Hamster Mucositis Study

Fifty-six (56) hamsters were given an acute radiation dose of 40 Gydirected to their oral mucosa on day 0. Test materials (each of theabove formulations A–F were applied topically beginning the day beforeradiation (day −1) and continuing until 20 days following radiation (day20). The grade of mucositis was scored, beginning on day 6, and forevery second day thereafter, until the end of the study on day 28. Theeffect on mucositis of each treatment group was compared to the salinecontrol. Each animal was scored according to a mucositis scale (0–5) inwhich 0 represents no mucositis, 5 represents severe mucositis, and ascore of three or above indicating that ulceration was observed. Themean of scores of animals in each group was recorded, and the number ofdays hamsters in each group have severe (score>3) mucositis wascalculated. Treatment efficacy was defined as a statisticallysignificant lower number of hamsters with this score in a drug treatmentgroup, versus control as determined by chi-square analysis. FIG. 4summarizes the result of a comparison of the formulations described inexample 9.

Those skilled in the art will recognize that, while specific embodimentsand examples have been described, various modifications and changes maybe made without departing from the scope and spirit of this invention.

1. A pseudoplastic liquid composition for treating or inhibiting an oralmucocutaneous disorder, said pseudoplastic liquid composition having azero shear viscosity at 37±1 degrees Celsius of 100-20,000 centipoise,comprising 0.1 to 2.0 wt/wt% of one or more mucoadhesives, wherein themucoadhesive(s) is/are selected from the group consisting ofpolyvinylpyrrolidone, carboxymethylcellulose, dextran sulfate,hydroxyalkylcellulose, dermatan sulfate, a water-soluble vinyl polymer,chitosan, guar gum, xanthan gum, tragacanth gum, pectin and polyacrylicacid; wherein said pseudoplastic viscous liquid composition, whenadministered to an oral mucosa: 1) remains liquid when shear is applieddue to swishing the liquid in the mouth; and 2) attaches to and coatsthe oral mucosa upon discontinuance of said shear.
 2. The pseudoplasticliquid composition of claim 1, wherein the mucoadhesive is cross-linkedpolyacrylic acid.
 3. The pseudoplastic liquid composition of claim 2,wherein the mucoadhesive is selected from the group consisting ofcarbopol or polycarbophil.
 4. The pseudoplastic liquid composition ofclaim 1, wherein the mucositis is erythema or ulceration induced bychemotherapy or radiation therapy.
 5. The pseudoplastic liquidcomposition of any one of claims 1 or 2, further comprising apreservative with antibacterial activity.
 6. The pseudoplastic liquidcomposition of claim 5, wherein the preservative is selected from thegroup consisting of methyl parabens, propyl parabens, benzyl alcohol,phenoxyethanol and mixtures thereof.
 7. The pseudoplastic liquidcomposition of any one of claim 1 or 2, further comprising one or moreviscosity-inducing agent(s).
 8. The pseudoplastic liquid composition ofclaim 7, wherein the viscosity-inducing agent is selected from the groupconsisting of an inorganic salt of a monovalent, divalent or trivalentcation.
 9. The pseudoplastic liquid composition of claim 8, wherein theinorganic salt is selected from the group consisting ofpharmaceutically-acceptable sodium, potassium, calcium, magnesium, zincor aluminum chloride, bromide, phosphate, borate, tartrate or benzoate.10. The pseudoplastic liquid composition of claim 7, wherein theviscosity-inducing agent is selected from the group consisting of agar,bentonite, glycerin, povidone, kaolin, tragacanth and sodium alginate.11. The pseudoplastic liquid composition of any one of claims 1 or 2,further comprising one or more pharmaceutically-acceptable excipients.12. The pseudoplastic liquid composition of claim 11, wherein thepharmaceutically-acceptable excipient(s) is/are selected from the groupconsisting of a preservative, a humectant, an emulsifying agent, anantioxidant, an antimicrobial agent, a solubilizing agent, a flavoringagent and a sweetening agent.
 13. The pseudoplastic liquid compositionof claim 1 wherein the amount of mucoadhesive is 0.35 weight percent.14. A pseudoplastic liquid composition for treating or inhibiting anoral mucocutaneous disorder, said liquid composition having a zero shearviscosity at 37±1 degrees Celsius of 100-20,000 centipoise, said liquidcomposition comprising 5% by weight of glycerine, 0.35% by weight ofcarbopol, 0.35% by weight of potassium hydroxide, and about 1 .5% byweight of benzyl alcohol; wherein said viscous liquid composition, whenadministered to an oral mucosa: 1) remains liquid when shear is applieddue to swishing the liquid in the mouth; and 2) attaches to and coatsthe oral mucosa upon discontinuance of said shear.
 15. A pseudoplasticliquid composition of claim 1, 13 or 14, wherein the compositionprovides a mean Son is scale rating of less than 1 when contacted withthe oral mucosa of a subject suffering from mucositis.
 16. Thepseudoplastic liquid composition of claim 15, wherein the subjectsuffering from mucositis is a cancer patient undergoing cancer therapy.